Basic drug compositions with enhanced bioavailability

Abstract

A composition comprising a basic drug, a drug which forms a zwitterion, or a salt of either entity, admixed with a polymer selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP). The compositions having improved solubility, hence bioavailability, in the small intestine; Processes for testing such compositions, and methods of using such compositions. The compositions comprise the basic drug, zwitterion, or salt and one or more of the aforementioned polymers. The invention further relates to a method for increasing the bioavailability of a basic or a zwitterionic drug comprising co-administering the basic drug, the zwitterionic drug, or the salt, with one or more of the aforementioned polymers.

What is claimed is:  
     
       1. A composition comprising 
       a) a basic drug, a drug which forms a zwitterion, or a salt of either, wherein said basic drug, zwitterionic drug, or salt of either is amorphous, admixed with  
       b) a polymer selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP);  
       wherein said basic drug, zwitterionic drug, or salt of either has a dose to aqueous solubility ratio greater than 100 at pH 5.0 to 7.0;  
       wherein, in the absence of said polymer, said basic drug, zwitterionic drug or salt has a solubility in a first aqueous use environment having a pH of 1.0 to 2.0 which is at least 3-fold the solubility of said drug in a second aqueous use environment having a pH in the range of 5.0 to 7.0;  
       and wherein, in said composition, said polymer is present in an amount such that, at any time during the first two hours following the time at which said composition has been introduced from said first use environment into said second use environment, the concentration of said dissolved basic drug, zwitterionic drug, or salt of either in said second use environment is at least 1.5-fold the concentration of said dissolved basic drug, zwitterionic drug, or salt introduced from said first environment into said second environment in a control composition not containing said polymer.  
     
     
       2. A composition as defined in  claim 1 , wherein said use environment is the gastrointestinal tract. 
     
     
       3. A composition as defined in  claim 1 , wherein said, use environment is in vitro aqueous test medium. 
     
     
       4. A composition as defined in  claim 1 , wherein said polymer increases the concentration of said dissolved basic drug, zwitterionic drug, or salt of either in said second use environment to at least 2-fold the concentration of said dissolved basic drug, zwitterionic drug, or salt introduced from said first environment into said second environment in a control composition not containing said polymer. 
     
     
       5. A composition as defined in  claim 1 , wherein said polymer increases the concentration of said dissolved basic drug, zwitterionic drug, or salt of either in said second use environment to at least 5-fold the concentration of said dissolved basic drug, zwitterionic drug, or salt introduced from said first environment into said second environment in a control composition not containing said polymer. 
     
     
       6. A composition as defined in  claim 1 , wherein said polymer is selected from HPMCAS and CAT. 
     
     
       7. A composition as defined in  claim 6 , wherein said polymer is HPMCAS. 
     
     
       8. A composition comprising a basic drug, a zwitterionic drug, or a salt of either, wherein said basic drug, zwitterionic drug, or salt of either is amorphous, admixed with a polymer selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP); 
       wherein said basic drug, zwitteronic drug, or salt of either has a dose to aqueous solubility ratio greater than 100 at pH 5.0 to 7.0; and  
       wherein, when said composition is dissolved in an aqueous in vitro test medium having a pH of 1.0 to 2.0, and said test medium is then adjusted to a pH between 5.0 and 7.0, the concentration of said drug in said aqueous pH 5-7 test medium, at any time during the first two hours following said pH adjustment, is at least 1.5-fold the concentration of said drug in a control aqueous test medium not containing said polymer.  
     
     
       9. A composition as defined in  claim 8 , wherein the concentration of said drug in said aqueous pH 5-7 test medium, at any time during the first two hours following said pH adjustment, is at least 2-fold the concentration of said drug in a control aqueous test medium not containing said polymer. 
     
     
       10. A composition as defined in  claim 8 , wherein the concentration of said drug in said aqueous pH 5-7 test medium, at any time during the first two hours following said pH adjustment, is at least 5-fold the concentration of said drug in a control aqueous test medium not containing said polymer. 
     
     
       11. A composition as defined in  claim 8 , wherein said polymer is selected from HPMCAS and CAT. 
     
     
       12. A composition as defined in  claim 11 , wherein said polymer is HPMCAS. 
     
     
       13. A composition comprising 
       a basic drug, a drug which forms a zwitterion, or a salt of either, wherein said basic drug, zwitterionic drug, or salt of either is amorphous, admixed with  
       a polymer selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP);  
       wherein said basic drug, zwitterionic drug, or salt of either has a dose to aqueous solubility ratio greater than 100 at pH 5.0 to 7.0;  
       said composition effecting in vivo either a maximum drug concentration in serum or plasma of a test subject (Cmax) or an area under the curve (AUC) plotting the serum or plasma concentration of drug along the ordinate (Y-axis) against time along the abscissa (X-axis) that is at least 1.25 times the corresponding Cmax or AUC effected by a control composition comprising an equivalent quantity of drug and excipients, but without said polymer.  
     
     
       14. A composition as defined in  claim 13 , which effects a coefficient of variation of Cmax or AUC which is at least 10% less than the coefficient of variation of Cmax and/or AUC observed for said control composition. 
     
     
       15. A composition as defined in  claim 13 , wherein said Cmax or AUC of said polymer-containing composition is at least 1.5 times the corresponding control Cmax or AUC. 
     
     
       16. A composition as defined in  claim 13 , wherein the Cmax or AUC of said polymer-containing composition is at least 2.0 times the corresponding control Cmax or AUC. 
     
     
       17. A composition as defined in  claim 13 , wherein both said Cmax and AUC are at least 1.5 times the corresponding control Cmax and AUC. 
     
     
       18. A composition as defined in  claim 14 , wherein said coeffient of variation for both Cmax and AUC is at least 10% less than the corresponding coefficients of variation for Cmax and AUC observed for said control composition. 
     
     
       19. A composition as defined in  claim 13 , wherein said polymer is selected from HPMCAS and CAT. 
     
     
       20. A composition as defined in  claim 19 , wherein said polymer is HPMCAS. 
     
     
       21. A method of administering a basic drug, a drug which forms a zwitterion, or a salt of either, wherein said basic drug, zwitterionic drug, or salt of either is amorphous, comprising co-administering, to a patient in need of said drug: 
       a) said basic drug, zwitterionic drug, or salt of either, wherein said basic drug, zwitterionic drug, or salt of either has a dose to aqueous solubility ratio greater than 100 at pH 5.0 to 7.0; and  
       b) a polymer selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP);  
       wherein, in the absence of said polymer, said basic drug, zwitterionic drug or salt of either has a solubility in a first aqueous use environment having a pH of 1.0 to 2.0 which is at least 3-fold the solubility of said drug in a second aqueous use environment having a pH in the range of 5.0 to 7.0;  
       and wherein said polymer is co-administered in an amount such that, at any time during the first two hours following the time at which said basic drug, zwitterionic drug, or salt of either has been introduced from said first use environment into said second use environment, the concentration of said basic drug, zwitterionic drug, or salt of either in said second use environment is increased to at least 1.5-fold the concentration of said basic drug, zwitterionic drug, or salt introduced from said first environment into said second environment in a control composition not containing said polymer.  
     
     
       22. A method as defined in  claim 21 , wherein said polymer increases the concentration of said dissolved basic drug, zwitterionic drug, or salt of either in said second use environment to at least 2-fold the concentration of said dissolved basic drug, zwitterionic drug, or salt introduced from said first environment into said second environment in a control composition not containing said polymer. 
     
     
       23. A method as defined in  claim 21 , wherein said polymer increases the concentration of said dissolved basic drug, zwitterionic drug, or salt of either in said second use environment to at least 5-fold the concentration of said dissolved basic drug, zwitterionic drug, or salt introduced from said first environment into said second environment in a control composition not containing said polymer. 
     
     
       24. A method as defined in  claim 21 , wherein said basic drug, zwitterionic drug, or salt of either is administered separately from said polymer. 
     
     
       25. A method as defined in  claim 24 , wherein said basic drug, zwitterionic drug, or salt of either and said polymer are administered at essentially the same time. 
     
     
       26. A method as defined in  claim 21 , wherein said basic drug, zwitterionic drug, or salt of either is administered in a composition also composing said polymer admixed therein. 
     
     
       27. A composition as defined in  claim 21 , wherein said polymer is selected from, HPMCAS and CAT. 
     
     
       28. A composition as defined in  claim 27 , wherein said polymer is HPMCAS. 
     
     
       29. A composition comprising 
       a) a basic drug, a drug which forms a zwitterion, or a salt of either, wherein said basic drug, zwitterionic drug, or salt of either is crystalline, admixed with  
       b) a polymer selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP);  
       wherein, in the absence of said polymer, said basic drug, zwitterionic drug or salt has a solubility in a first aqueous use environment having a pH of 1.0 to 2.0 which is at least 3-fold the solubility of said drug in a second aqueous use environment having a pH in the range of 5.0 to 7.0;  
       and wherein, in said composition, said polymer is present in an amount such that, at any time during the first two hours following the time at which said composition has been introduced from said first use environment into said second use environment, the concentration of said dissolved basic drug, zwitterionic drug, or salt of either in said second use environment is at least 1.5-fold the concentration of said dissolved basic drug, zwitterionic drug, or salt introduced from said first environment into said second environment in a control composition not containing said polymer.  
     
     
       30. A composition comprising a basic drug, a zwitterionic drug, or a salt of either, wherein said basic drug, zwitterionic drug, or salt of either is crystalline, admixed with a polymer selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP); 
       wherein, when said composition is dissolved in an aqueous in vitro test medium having a pH of 1.0to 2.0, and said test medium is then adjusted to a pH between 5.0 and 7.0, the concentration of said drug in said aqueous pH 5-7 test medium, at any time during the first two hours following said pH adjustment, is at least 1.5-fold the concentration of said drug in a control aqueous test medium not containing said polymer.  
     
     
       31. A composition comprising 
       a basic drug, a drug which forms a zwitterion, or a salt of either, wherein said basic drug, zwitterionic drug, or salt of either is crystalline, admixed with  
       a polymer selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP);  
       said composition effecting in vivo either a maximum drug concentration in serum or plasma of a test subject (Cmax) or an area under the curve (AUC) plotting the serum or plasma concentration of drug along the ordinate (Y-axis) against time along the abscissa. (X-axis) that is at least 1.25 times the corresponding Cmax or AUC effected by a control composition comprising an equivalent quantity of drug and excipients, but without said polymer.  
     
     
       32. A method of administering a basic drug, a drug which forms a zwitterion, or a salt of either, wherein said basic drug, zwitterionic drug, or salt of either is crystalline, comprising co-administering, to a patient in need of said drug: 
       a) said basic drug, zwitterionic drug, or salt of either; and  
       b) a polymer selected from hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate (CAT), cellulose acetate phthalate (CAP), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethyl-cellulose acetate phthalate (HPMCAP), and methylcellulose acetate phthalate (MCAP);  
       wherein, in the absence of said polymer, said basic drug, zwitterionic drug or salt of either has a solubility in a first aqueous use environment having a pH of 1.0 to 2.0 which is at least 3-fold the solubility of said drug in a second aqueous use environment having a pH in the range of 5.0 to 7.0;  
       and wherein said polymer is co-administered in an amount such that, at any time during the first two hours following the time at which said basic drug, zwitterionic drug, or salt of either has been introduced from said first use environment into said second use environment, the concentration of said basic drug, zwitterionic drug, or salt of either in said second use environment is increased to at least 1.5-fold the concentration of said basic drug, zwitterionic drug, or salt introduced from said first environment into said second environment in a control composition not containing said polymer.  
     
     
       33. A composition as defined in  claim 29 , wherein said basic drug, zwitterionic drug, or salt of either has a dose to aqueous solubility ratio greater than 100 at pH 5.0 to 7.0. 
     
     
       34. A composition as defined in  claim 29 , wherein said use environment is the gastrointestinal tract. 
     
     
       35. A composition as defined in  claim 29 , wherein said use environment is in vitro aqueous test medium. 
     
     
       36. A composition as defined in  claim 29 , wherein said polymer increases the concentration of said dissolved basic drug, zwitterionic drug, or salt of either in said second use environment to at least 2-fold the concentration of said dissolved basic drug, zwitterionic drug, or salt introduced from said first environment into said second environment in a control composition not containing said polymer. 
     
     
       37. A composition as defined in  claim 29 , wherein said polymer increases the concentration of said dissolved basic drug, zwitterionic drug, or salt of either in said second use environment to at least 5-fold the concentration of said dissolved basic drug, zwitterionic drug, or salt introduced from said first environment into said second environment in a control composition not containing said polymer. 
     
     
       38. A composition as defined in  claim 29 , wherein said polymer is selected from HPMCAS, CAT, and CAP. 
     
     
       39. A composition as defined in  claim 38 , wherein said polymer is HPMCAS. 
     
     
       40. A composition as defined in  claim 30 , wherein the concentration of said drug in said aqueous pH 5-7 test medium, at any time during the first two hours following said pH adjustment, is at least 2-fold the concentration of said drug in a control aqueous test medium not containing said polymer. 
     
     
       41. A composition as defined in  claim 30 , wherein the concentration of said drug in said aqueous pH 5-7 test medium, at any time during the first two hours following said pH adjustment, is at least 5-fold the concentration of said drug in a control aqueous test medium not containing said polymer. 
     
     
       42. A composition as defined in  claim 30 , wherein said basic drug, zwitterionic drug, or salt of either has a dose to aqueous solubility ratio greater than 100 at pH 6.5. 
     
     
       43. A composition as defined in  claim 30 , wherein said polymer is selected from HPMCAS, CAT, and CAP. 
     
     
       44. A composition as defined in  claim 43 , wherein said polymer is HPMCAS. 
     
     
       45. A composition as defined in  claim 31 , which effects a coefficient of variation of Cmax or AUC which is at least 10% less than the coefficient of variation of Cmax and/or AUC observed for said control composition. 
     
     
       46. A composition as defined in  claim 31 , wherein said Cmax or AUC of said polymer-containing composition is at least 1.5 times the corresponding control Cmax or AUC. 
     
     
       47. A composition as defined in  claim 31 , wherein the Cmax or AUC of said polymer-containing composition is at least 2.0 times the corresponding control Cmax or AUC. 
     
     
       48. A composition as defined in  claim 31 , wherein both said Cmax and AUC are at least 1.5 times the corresponding control Cmax and AUC. 
     
     
       49. A composition as defined in  claim 45 , wherein said coeffient of variation for both Cmax and AUC is at least 10% less than the corresponding coefficients of variation for Cmax and AUC observed for said control composition. 
     
     
       50. A composition described in  claim 31 , wherein said basic drug, zwitterionic drug, or salt of either has a dose to aqueous solubility ratio greater than 100 at pH 6.5. 
     
     
       51. A composition as defined in  claim 31 , wherein said polymer is selected from HPMCAS, CAT, and CAP. 
     
     
       52. A composition as defined in  claim 51 , wherein said polymer is HPMCAS. 
     
     
       53. A method as defined in  claim 32 , wherein said polymer increases the concentration of said dissolved basic drug, zwitterionic drug, or salt of either in said second use environment to at least 2-fold the concentration of said dissolved basic drug, zwitterionic drug, or salt introduced from said first environment into said second environment in a control composition not containing said polymer. 
     
     
       54. A method as defined in  claim 32 , wherein said polymer increases the concentration of said dissolved basic drug, zwitterionic drug, or salt of either in said second use environment to at least 5-fold the concentration of said dissolved basic drug, zwitterionic drug, or salt introduced from said first environment into said second environment in a control composition not containing said polymer. 
     
     
       55. A method as defined in  claim 32 , wherein said basic drug, zwitterionic drug, or salt of either is administered separately from said polymer. 
     
     
       56. A method as defined in  claim 55 , wherein said basic drug, zwitterionic drug, or salt of either and said polymer are administered at essentially the same time. 
     
     
       57. A method as defined in  claim 32 , wherein said basic drug, zwitteronic drug, or salt of either is administered in a composition also comprising said polymer admixed therein. 
     
     
       58. A composition as described in  claim 32 , wherein said basic drug, zwitterionic drug, or salt of either has a dose to aqueous solubility ratio greater than 100 at pH 6.5. 
     
     
       59. A composition as defined in  claim 32 , wherein said polymer is selected from HPMCAS, CAT, and CAP. 
     
     
       60. A composition as defined in  claim 59 , wherein said polymer is HPMCAS.